(1). Genomic expression profile of metastatic spread of thyroid cancer mediated by the oncogenic action of TRbetaPV. Metastasis is the major cause of thyroid cancer-related death. However, little is known about the genes involved in the metastatic spread of thyroid carcinomas. To uncover genes destined to drive the metastatic process in the thyroid cancer of TRbetaPV/PV mice, we used cDNA microarrays to compare the genomic expression profile of laser capture microdissected thyroid tumor lesions of TRbetaPV/PV mice with that of hyperplastic thyroid cells of wild-type mice having elevated TSH induced by treatment with propylthiouracil (PTU;WT-PTU mice). Analyses of microarray data indicated that the expressions of 150 genes were significantly altered between TRbetaPV/PV mice and WT-PTU mice (87 genes had higher expression and 63 genes had lower expression in TRbetaPV/PV mice than in WT-PTU mice). Thirty-six percent of genes with altered expression function as key regulators in metastasis. The remaining genes are involved in various cellular processes including metabolism, intracellular trafficking, transcriptional regulation, post-transcriptional modification, and cell-cell/extracellular matrix signaling. Our studies have uncovered novel genes responsible for the metastatic spread of follicular thyroid cancer and, furthermore, have shown that the metastatic process of thyroid cancer requires effective collaboration among genes with diverse cellular functions. Importantly, our studies indicate that the tumor cells in the primary lesions are endowed with the genes destined to promote metastasis. Thus, our study has provided new insights into the metastatic spread of human thyroid cancer. The novel genes uncovered for the metastatic spread of follicular thyroid cancer could be tested as potential molecular targets for treatment. (2). Global expression profiling reveals gain-of-function oncogenic activity of a mutated thyroid hormone receptor (TRbetaPV) in thyroid carcinogenesis. To understand whether oncogenic actions of PV involve not only the loss of normal TR functions but also gain-of-function activities, we compared the gene expression profiles of thyroid lesions in TRbetaPV/PV mice and TRalpha-/-TRbeta-/- mice that also spontaneously develop FTC, but with less severe malignancy. Analysis of the cDNA microarray data derived from microdissected thyroid tumor cells of these two mice showed contrasting global gene expression profiles. With stringent selection using 2.5-fold change (p&lt;0.01) in cDNA microarray analysis, 241 genes with altered gene expression were identified. Nearly half of the genes (n=113: 49% of total) with altered gene expression in thyroid tumor cells of TRbetaPV/PV mice were associated with tumorigenesis and metastasis;some of these genes function as oncogenes in human thyroid cancers. The remaining genes were found to function in transcriptional regulation, RNA processing, cell proliferation, apoptosis, angiogenesis, and cytoskeleton modification. These results indicate that the more aggressive thyroid tumor progression in TRbetaPV/PV mice was not due simply to the loss of tumor suppressor functions of TR via mutation but also, importantly, to gain-of-function in the oncogenic activities of PV to drive thyroid carcinogenesis. Thus, the present study identifies a novel mechanism by which a mutated TRbeta evolves with an oncogenic advantage to promote thyroid carcinogenesis. (3). Tumor suppressor action of liganded thyroid hormone receptor beta by direct repression of beta-catenin gene expression. The abundance of beta-catenin, which plays a critical role in oncogenesis, is tightly controlled by proteasomal pathways. Its aberrant accumulation is associated with the overactivation of its oncogenic signaling and tumorigenesis in cancers, including thyroid cancer. Our previous studies have suggested that beta-catenin abundance could also be regulated at the transcriptional level by T3 and TRbeta. By using hypothyroid mice supplemented or not with T3, we showed that T3 significantly repressed Ctnnbeta1 expression in vivo in the mouse thyroid. By using two human cell lines, i.e., the thyroid HTori and the cervical cancer HeLa cell lines, each stably expressing TRbeta, we observed that T3 induced the down-regulation of CTNNB1 transcript levels. Luciferase reporter assays with various constructs harboring 5 deletion of the CTNNB1 promoter, and electrophoretic mobility shift assays further showed that this transrepression was mediated through an interaction between TRbeta-RXRbeta complexes and TREs located in the human CTNNB1 promoter between -807 and -772, and consisting of two hexamers separated by 14 nucleotides. The direct regulation of CTNNB1 expression by TRbeta was further confirmed by chromatin immunoprecipitation assays showing TRbeta recruitment to the CTNNB1 promoter in thyroid cells. This is the first report demonstrating a direct repression of the beta-catenin gene by liganded TRbeta through interaction with negative TREs located in CTNNB1 promoter. Importantly, this study uncovers a new molecular mechanism whereby liganded TRbeta acts as a tumor suppressor via inhibition of the expression of a potent tumor promoter, the CTNNB1 gene. (4). Mutation of thyroid hormone receptor in mice predisposes to the development of mammary tumors. Correlative data suggest that TRbeta mutations could increase the risk of mammary tumor development, but unequivocal evidence is still lacking. To explore the role of TRbeta mutants in vivo in breast tumor development and progression, we took advantage of TRbetaPV/PV mice. In adult nulliparous females, a single TRbetaPV allele did not contribute to mammary gland abnormalities, but the presence of two TRbetaPV alleles led to mammary hyperplasia in 36% of TRbetaPV/PV mice. The TRbetaPV mutation further markedly augmented the risk of mammary hyperplasia in a mouse model with high susceptibility to mammary tumors (Pten+/-), as demonstrated by the occurrence of mammary hyperplasia in 60 % of TRbetaPV/+ Pten+/- mice and 77% of TRbetaPV/PVPten+/- mice versus 33% of TRbeta+/+ Pten+/- mice. The PV mutation increased the activity of signal transducer and activator of transcription (STAT5) to increase cell proliferation and the expression of the STAT5 target genes. Further studies showed that T3 repressed STAT5 signaling in TRbeta-expressing cells through decreasing STAT5-mediated transcription activity and target gene expression, whereas sustained STAT5 signaling was observed in TRbetaPV-expressing cells. Collectively, these findings show for the first time that a TRbeta mutation promotes the development of mammary hyperplasia via aberrant activation of STAT5, thereby conferring a fertile genetic ground for tumorigenesis.